Since the advent of cisplatin (I) in the late 1960s, platinum complexes have become a mainstay in the practitioner's arsenal of anti-tumor chemotherapeutics. They find use, either alone or in combination with other chemotherapeutic agents, against virtually all solid tumor cancers. All current clinical platinum complex chemotherapeutics share the generic structure of cisplatin; i.e., Pt(L1)(L2)(L3)(L4), in which L1 and L2 represent two stable cis-monodentate am(m)ine ligands or, as L1-L2, a stable bidentate amine ligand and L3 and L4 represent two monodentate anionic leaving-ligands or, as L3-L4, a bidentate anionic leaving-ligand. Despite their ability to react with many different biomolecules, the mode of action of the Pt complex drugs is presently accepted as involving hydrolytic loss of the anionic leaving-ligands with concomitant formation of the much more reactive aqua (water) ligand complex, which is capable of reacting with DNA to form intra- and inter-strand cross-links, leading to cell death. The usefulness of cisplatin is limited by its therapeutic index (the ratio of the maximum tolerable dose to minimum effective dose), which tends to be relatively low due to the toxicity of the active aqua species and the rapidity with which it forms in vivo. Among the approaches that have been employed to improve the therapeutic index of cisplatin, two have predominated. The first had been to use anionic leaving-ligands that are more stable to hydrolytic cleavage so that the aqua species does not form until the compound has infiltrated a target tumor. To date, this approach has resulted in four clinical platinum complex compounds that exhibit improved pharmaceutical characteristics compared to cisplatin: carboplatin (II), oxaliplatin (III), nedaplatin (IV) and lobaplatin (V).

The second approach, often used in conjunction with the first, is targeting; i.e., combining the platinum complex with a compound that preferentially accumulates in tumors so that, once it passively encounters a tumor or a compound that has a specific affinity for a molecule or receptor expressed on the surface of a neoplastic cell but not a healthy cell. Preferential accumulation in tumors can be achieved by using compounds that take advantage of the “enhanced permeability and retention” (EPR) effect operative in tumors.
Briefly, the EPR effect, which was first described with regard to the preferential permeation into, and retention by, tumor tissues of serum proteins, is the result of defective tissue architecture, changes in permeation mediators and impaired lymphatic drainage in tumors. That is, the vascular endothelium of tumors tends to have relatively large gaps in the endothelial cell-cell junctions compared to normal tissue. This permits larger molecular species to permeate the tissue than is the case for healthy tissue. The altered permeation mediators and impaired lymphatic drainage mechanism then assure that the molecules that have penetrated the tumor stay there. The EPR effect has been used in practice to selectively introduce and retain chemotherapeutics in tumors by tethering small molecule drugs to polymers or nanoparticles that are too large to permeate normal tissue but that readily infiltrate tumor tissue.
For example, U.S. Pat. No. 5,965,118, assigned to Access Pharmaceuticals, Inc., claims an polyacrylamide or polymethacrylamide backbone polymer wherein a portion of the pendant amide groups are linked by a peptide chain to a terminal platinum complex. The remainder of the pendant amide groups are substituted with a water-solubilizing hydroxyalkyl group. The size of the polymer is optimized to be large enough to take advantage of the EPR effect, yet small enough so that any drug remaining in the circulatory system is susceptible to renal elimination. The anionic leaving ligands through which the Pt species are bound to the polymer are bidentate carboxyl or aminoethylamido groups in the '118 patent. The polymer-bound platinum complex is passively transported to the target tumor through the vascular system until it preferentially enters into and is retained in tumors due to the EPR effect where hydrolytic cleavage to an active small molecule aqua species occurs.
U.S. Pat. No. 6,692,734, also assigned to Access Pharmaceuticals, Inc., likewise claims polymer-bound platinum complexes, the difference being that the Pt is bound to the polymer by bidentate N,O-amidomalonate ligands rather than bidentate aminoethylamide or bidentate carboxyl ligands.
What is needed is new, more potent and efficacious Pt complex chemotherapeutics having superior therapeutic indices. The present invention provides such compounds.